The acute intraperitoneal LD50 of theophylline in rats was reported to be 206 mg/kg bw, and accompanying clinical signs were delayed convulsions and tetanic spasm. Acute studies in mice showed an oral LD50 of 332 mg/kg bw and an intraperitoneal LD50 of 217 mg/kg bw; clinical signs included convulsions, profuse salivation and emesis (Tarka, 1982).
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A single oral dose of 400 mg/kg bw theophylline was acutely toxic to rats and mice. Administration of the same daily dose as two separate doses of 200 mg/kg bw was acutely toxic to rats but not to mice (Lindamood et al., 1988). In dogs, the minimal oral toxic concentration of theophylline appears to be higher (37–60 µg/ml plasma) than in man (> 20 µg/ml) (Munsiff et al., 1988b). Theophylline has been reported to be more toxic than caffeine or theobromine to the heart, bronchi and kidneys (Tarka, 1982).
Two weeks’ feeding 800 ppm (mg/kg) theophylline in the diet to rats induced no significant toxicity except for dose-related uterus hypoplasia (Lindamood et al., 1988).
Reproductive toxicity: Feeding theophylline to immature (five to six weeks old) Osborne-Mendel rats at 0.5% in the diet [approximately 300 mg/kg bw per day] for 75 weeks produced severe testicular atrophy in 50% of animals, oligo-spermatogenesis and aspermatogenesis. These results were confirmed in Holtzman rats fed 0.5% theophylline for 19 weeks: 86% showed testicular atrophy (Friedman et al., 1979).
In 13-week toxicity studies, weanling B6C3F1 mice and Fischer 344 rats were administered theophylline by gavage or in the diet. Gavage with 300 mg/kg bw per day led to a slight but significant decrease in testicular weight in mice, but 150 mg/kg bw or less had no effect. In rats, a significant decrease in testicular weight was observed after gavage with 150 mg/kg bw per day but not with 75 mg/kg bw or less. No effect on sperm motility, sperm density or the number of abnormal sperm was observed in male rats or mice, and no effect was seen on the mean length of the oestrous cycle in females. Daily administration of 184–793 mg/kg bw theophylline in the diet to mice had no effect on sperm, whereas abnormal sperm were seen in rats given 258 mg/kg in the diet but not at lower doses (Morrissey et al., 1988).
In a reproductive study, Swiss CD-1 mice were administered 0.075, 0.15 or 0.30% theophylline in the diet (average daily doses, 125, 265 or 530 mg/kg bw) for one week before mating and during 13 weeks of cohabitation. Litters were removed one day after birth, except for the last litter which was raised to 21 days of age. Among all treated groups, there was a dose-related decrease in the number of live pups per litter; in the high-dose groups, there was a significant decrease in the number of litters per breeding pair and a significant decrease in live pup weight. In the high- and mid-dose groups, a significant decrease in the percentage of pups born alive was observed. Only mild toxicity was observed in adults at these doses. In a cross-over mating trial at the end of a 19-week exposure to 0.3% theophylline, animals of each sex were found to be affected, although females were more severely affected than males. The decrease in reproductive capacity was considered by the authors to be related partially to embryotoxicity (Morrissey et al., 1988).
Developmental toxicity. IRC-JCL mice received a single intraperitoneal injection of 175, 200 or 225 mg/kg bw theophylline on day 12 of gestation. Subsequently, 40% of dams in the high-dose group died, and dyspnoea and convulsions were observed in those in the low- and mid-dose groups. Fetal body weight was decreased with the high and medium doses, and the incidence of resorptions was significantly increased with the high dose. Malformations were observed in all treated groups; these included cleft palate, digital defects and macrognathia. Subcutaneous haematomas were also seen (Fujii & Nishimura, 1969).
ICR mice received an intraperitoneal injection of 100, 150 or 200 mg/kg bw theophylline on one of gestation days 10–13. A dose-related increase in the incidence of resorptions and malformations — mostly cleft palate — was observed, with a peak embryotoxic response in fetuses treated on day 11 (Tucci & Skalko, 1978).
Sprague-Dawley rats were fed theophylline in the diet (average daily dose, 124, 218 or 259 mg/kg bw) on days 6–15 of gestation. In parallel, Swiss CD-1 mice received theophylline in the drinking-water (daily doses, 282, 372 or 396 mg/kg bw) on the same gestation days. Slight maternal toxicity (decreased weight gain) was observed in high-dose rats and in mid- and high-dose mice. In rats, fetal body weight was significantly decreased with the medium and high doses, and live litter size was decreased with the high dose; no malformation was observed. In mice, fetal body weight was significantly decreased in the mid- and high-dose groups, and the incidence of resorptions was increased in the mid-dose group (Lindström et al., 1990).
Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors.[1] It is used to treat chronic obstructive pulmonary disease (COPD) and asthma.[2] Its pharmacology is similar to other methylxanthine drugs (e.g., theobromine and caffeine).[1] Trace amounts of theophylline are naturally present in tea, coffee, chocolate, yerba maté, guarana, and kola nut.[1][3]
The name 'theophylline' derives from "Thea"—the former genus name for tea + Legacy Greek φύλλον (phúllon, "leaf") + -ine.
Medical uses
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The main actions of theophylline involve:[2]
The main therapeutic uses of theophylline are for treating:[2]
Performance enhancement in sports
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Theophylline and other methylxanthines are often used for their performance-enhancing effects in sports, as these drugs increase alertness, bronchodilation, and increase the rate and force of heart contraction.[9] There is conflicting information about the value of theophylline and other methylxanthines as prophylaxis against exercise-induced asthma.[10]
Adverse effects
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The use of theophylline is complicated by its interaction with various drugs and by the fact that it has a narrow therapeutic window (<20 mcg/mL).[2] Its use must be monitored by direct measurement of serum theophylline levels to avoid toxicity. It can also cause nausea, diarrhea, increase in heart rate, abnormal heart rhythms, and CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness).[2][11] Seizures can also occur in severe cases of toxicity, and are considered to be a neurological emergency.[2]
Its toxicity is increased by erythromycin, cimetidine, and fluoroquinolones, such as ciprofloxacin. Some lipid-based formulations of theophylline can result in toxic theophylline levels when taken with fatty meals, an effect called dose dumping, but this does not occur with most formulations of theophylline.[12] Theophylline toxicity can be treated with beta blockers. In addition to seizures, tachyarrhythmias are a major concern.[13] Theophylline should not be used in combination with the SSRI fluvoxamine.[14][15]
Spectroscopy
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UV-visible spectroscopy
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Theophylline is soluble in 0.1N NaOH and absorbs maximally at 277 nm with an extinction coefficient of 10,200 (cm−1 M−1).[16]
Proton nuclear magnetic resonance spectroscopy (1H-NMR)
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The characteristic signals, distinguishing theophylline from related methylxanthines, are approximately 3.23δ and 3.41δ, corresponding to the unique methylation possessed by theophylline. The remaining proton signal, at 8.01δ, corresponds to the proton on the imidazole ring, not transferred between the nitrogen. The transferred proton between the nitrogen is a variable proton and only exhibits a signal under certain conditions.[17]
Carbon nuclear magnetic resonance spectroscopy (13C-NMR)
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The unique methylation of theophylline corresponds to the following signals: 27.7δ and 29.9δ. The remaining signals correspond to carbons characteristic of the xanthine backbone.[18]
Natural occurrences
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Theophylline is naturally found in cocoa beans. Amounts as high as 3.7 mg/g have been reported in Criollo cocoa beans.[19]
Trace amounts of theophylline are also found in brewed tea, although brewed tea provides only about 1 mg/L,[20] which is significantly less than a therapeutic dose.
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Trace amounts of theophylline are also found in guarana (Paullinia cupana) and in kola nuts.[21]
Pharmacology
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Pharmacodynamics
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Like other methylated xanthine derivatives, theophylline is both a
Pharmacokinetics
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Absorption
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When theophylline is administered intravenously, bioavailability is 100%.[27]
Distribution
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Theophylline is distributed in the extracellular fluid, in the placenta, in the mother's milk and in the central nervous system. The volume of distribution is 0.5 L/kg. The protein binding is 40%.[medical citation needed]
Metabolism
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Theophylline is metabolized extensively in the liver.[2] It undergoes N-demethylation via cytochrome P450 1A2. It is metabolized by parallel first order and Michaelis-Menten pathways. Metabolism may become saturated (non-linear), even within the therapeutic range. Small dose increases may result in disproportionately large increases in serum concentration. Methylation to caffeine is also important in the infant population. Smokers and people with hepatic (liver) impairment metabolize it differently.[2] Cigarette and marijuana smoking induces metabolism of theophylline, increasing the drug's metabolic clearance.[28][29]
Excretion
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Theophylline is excreted unchanged in the urine (up to 10%). Clearance of the drug is increased in children (age 1 to 12), teenagers (12 to 16), adult smokers, elderly smokers, as well as in cystic fibrosis, and hyperthyroidism. Clearance of the drug is decreased in these conditions: elderly, acute congestive heart failure, cirrhosis, hypothyroidism and febrile viral illnesses.[2]
The elimination half-life varies: 30 hours for premature neonates, 24 hours for neonates, 3.5 hours for children ages 1 to 9, 8 hours for adult non-smokers, 5 hours for adult smokers, 24 hours for those with hepatic impairment, 12 hours for those with congestive heart failure NYHA class I-II, 24 hours for those with congestive heart failure NYHA class III-IV, 12 hours for the elderly.[medical citation needed]
History
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Theophylline was first extracted from tea leaves and chemically identified around 1888 by the German biologist Albrecht Kossel.[30][31] Seven years later, a chemical synthesis starting with 1,3-dimethyluric acid was described by Emil Fischer and Lorenz Ach.[32] The Traube purine synthesis, an alternative method to synthesize theophylline, was introduced in 1900 by another German scientist, Wilhelm Traube.[33] Theophylline's first clinical use came in 1902 as a diuretic.[34] It took an additional 20 years until it was first reported as an asthma treatment.[35] The drug was prescribed in a syrup up to the 1970s as Theostat 20 and Theostat 80, and by the early 1980s in a tablet form called Quibron.
References
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